14-3-3 proteins are abundantly expressed in the brain, particularly neuronal tissue and are thought to serve multiple biological functions involved in neuronal development and cell growth and death. Recent studies have shown associations of 14-3-3 genes with neurodegenerative disorders based on their chromosomal linkage to these diseases and to regulatory functions for the nervous system. Although the role of 14-3-3 proteins in the pathogenesis of prion diseases remains unknown, the detection of altered levels of isoforms of the 14-3-3 protein in the cerebrospinal fluid is considered a biomarker for diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). To identify other susceptibility genes for prion disease, we examined nucleotide variations in YWHAH, a gene encoding 14-3-3 eta. This case-control study included 182 sCJD patients and 206 healthy Koreans. Polymerase chain reaction was used to amplify open reading frame and some 3'-untranslated region (UTR) in exon 2, and direct sequencing was carried out. One polymorphism, 753 G/A, was detected in the 3'-UTR of exon 2 on the YWHAH. The genotype distribution and allele frequencies of the YWHAH 753 G/A polymorphism were not significantly different between controls and sCJD patients. This finding indicates that YWHAH 753 G/A polymorphism is unlikely to be linked to genetic susceptibility or have a modifying effect in sCJD. On analysis stratified by the prion protein gene 129 or 219 genotype, no significant relation was found in genotype and allele frequencies of the YWHAH 753G/A. This is the first genetic association study of YWHAH with sCJD populations.